The present invention relates to a process for preparing halides of N-acetylneuraminic acid which are particularly useful as a starting material for the preparation of new N-acetylneuraminic acid derivatives having an excellent immunological activity.
The halides of N-acetylneuraminic acid represented by the following general formula [I]: ##STR1## wherein R.sup.1 is a lower alkyl or a non-substituted or lower alkyl substituted aralkyl or aryl group, R.sup.2 and R.sup.3 represent hydrogen atom or acetyl group independently and hal represents a halogen atom,
particularly chlorides thereof are known as explained below. The compounds [I] are useful as a starting material for preparing immunologically active derivatives of N-acetylneuraminic acid which are clinically expected as an immunosuppressive, in particular to treat autoimmune disease such as collagenosis disease without causing any serious side-effects (see, for example Japanese Patent Application No. 77672/1981).
Therefore, it is medically and pharmaceutically important to develop a new, simple and economical process which provides the compounds [I] in high yield.
Conventionally, a known process for preparing the compounds [I] is the process of Richard Kuhn et al. disclosed in Chem. Ber., 99, 611 (1966) which comprises the steps of esterifying N-acetylneuraminic acid as a starting material to prepare methyl .beta.-D-N-acetylneuraminate (step 1), acetylating the acetylneuraminate derivative to obtain methyl 4,7,8,9-tetra-O-acetyl-.beta.-D-N-acetylneuraminate (step 2) and chlorinating said acetylated derivative to form methyl 2-chloro-4,7,8,9-tetra-O-acetyl-.beta.-D-N-acetylneuraminate (step 3).
According to the process of R. Kuhn et al., at the first step the esterified derivative may be obtained as a yield of 97% crude product and about 60% purified product and at the second step the objective acetylated derivative may be prepared by treating the esterified derivative with acetic anhydride under the presence of perchloric acid catalyst and extracting the product with chloroform, in an yield of 61%. However, in the re-examination carried out by the inventors of the present invention, the yield of said second step is found to be at most 60%. While at the third step the crude acetylated derivative is treated with acetylchloride solution saturated with hydrogen chloride gas at -40.degree. to -60.degree. C. under moderate pressure condition and the final product is obtained in a yield of 80%. However, in this third step, there are problems in economy and safety of the reaction condition.
Therefore, in the process of R. Kuhn et al. there still remains room for improvement.